In many countries, commercial livestock rearing systems have become commonplace. Commercial animal husbandry techniques have been used to rear, for example, livestock, poultry, and fish. These techniques have resulted in greatly increased production of food products from such animals. Successful commercial raising of animals, particularly for food, requires maximization of the growth rate and feed utilization efficiency to reduce the unit cost of production. This has led to the development and widespread use of feed additives.
Zilpaterol is a known adrenergic β-2 agonist corresponding in structure to Formula (I):
The IUPAC name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-(isopropylamino) imidazo[4,5,1-jk]-[1]benzazepin-2(1H)-one. The Chemical Abstracts name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-[(1-methyl-ethyl)amino]-imidazo[4,5,1-jk][1]benzazepin-2(1H)-one.
Zilpaterol hydrochloride is sold by Intervet Inc., a part of Schering-Plough Corporation, under the trademark ZILMAX®. It is approved in the United States for cattle fed in confinement for harvest at daily doses ranging from 60 to 90 mg/animal to increase the rate of weight gain, improve feed efficiency, and increase carcass leanness during the last 20 to 40 days on feed. See NADA No. 141-258.
In U.S. Pat. No. 4,585,770, Fréchet et al. discuss compounds, such as zilpaterol, encompassed by a genus characterized as 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-j-k][1]-benzazepin-2-(1H)-one derivatives and acid addition salts thereof. Fréchet et al. state that such compounds may be used as an active ingredient for inducing antihypertensive and hypotensive activity in a warm-blooded animal.
In U.S. Pat. No. 4,900,735, Grandadam discusses a zootechnical composition comprising zilpaterol and acid addition salts thereof. Grandadam states that such a composition may be used to increase the weight of cattle, pigs, sheep, and poultry. Grandadam also discusses combination therapies that further comprise the administration of a steroid corresponding in structure to Formula (II):
Here, X is selected from the group consisting of hydrogen, optionally unsaturated alkyl of 1 to 6 carbon atoms wherein one of the carbon atoms may be replaced by oxygen, and acyl of an organic carboxylic acid of 1 to 18 carbon atoms. Such compounds include trenbolone acetate, wherein X is —C(O)CH3. Trenbolone acetate is approved in the United States for use, alone and in combination with other active ingredients, in various implants in cattle to increase the rate of weight gain and improve feed efficiency. See NADA Nos. 138-612, 140-897, 140-992, 414-043, 141-269, 200-221, 200-224, 200-346, and 200-367. Grandadam goes onto discuss combinations that further comprise the administration of zeranol or estradiol (i.e., 17β-estra-1,3,5(10)-triene-3,17-diol). Zeranol is approved in the United States for use in implants to increase the rate of weight gain and improve feed efficiency in cattle and sheep. See NADA Nos. 038-233 and 141-0192. Estradiol and estradiol benzoate are approved in the United States for use in combination with other active ingredients in various implants for increasing the rate of weight gain and improving feed efficiency in cattle. See NADA Nos. 009-576, 011-427, 110-315, 118-123, 135-906, 140-897, 140-992, 141-043, 141-269, 200-221, 200-346, and 200-367.
In U.S. Pat. Nos. 5,731,028 and 5,847,124, Chevremont et al. discuss crystallized anhydrous zilpaterol hydrochloride, and particularly crystallized anhydrous zilpaterol hydrochloride wherein less than 5% of the crystals have a size of less than 15 μm, and at least 95% of the crystals have a size of less than 250 μm. According to Chevremont et al., such crystals may be incorporated into animal feed to increase body weight and meat quality. Chevremont et al. provide methods for making such crystals, and discuss using the crystals to make animal premixes in which the crystals are secured to a corn cob support having a greater particle size. They also discuss monohydrate and trihydrate intermediates that can be useful in, for example, making the crystals.
In U.S. Pat. No. 7,207,289, Montgomery discusses methods for increasing beef production, reducing feed intake while maintaining beef production, and reducing incidences of liver abscess in cattle. These methods comprise administering a feed comprising an ionophore and macrolide antibiotic during an initial period, and then administering a feed comprising zilpaterol (including zilpaterol hydrochloride) with essentially no ionophore or macrolide antibiotic
Melengestrol acetate (or “17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione”) corresponds in structure to Formula (III):
It is reported to be an orally-active progestogen that inhibits estrus and ovulation, and increases weight gain in heifers. It is commercially available from Pfizer Animal Health under the trade name MGA®. U.S. Pat. No. 3,359,287 discusses preparation of melengestrol acetate by dehydrogenating 17α-hydroxy-6α-methyl-16-methylenepregn-4-ene-3,20-dione 17-acetate with chloranil. U.S. Pat. No. 4,154,748 discusses an alternative process wherein melengestrol acetate is prepared by a process comprising acetylation of 17α-hydroxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione.
Melengestrol acetate is approved in the United States for feeding to heifers for harvest at doses ranging from 0.25 to 0.50 mg/heifer daily to increase weight gain, improve gain efficiency, and suppress estrus. See NADA 034-254, 039-402, and 200-343. It is generally fed to heifers for 90 to 150 days before harvest. It also has been approved in the United States for the following combinations:                a) With oxytetracycline to increase the rate of weight gain, improve feed efficiency, suppress estrus, and reduce liver condemnation due to liver abscesses. See NADA 046-718 and 046-719        b) With monensin sodium to increase the rate of weight gain, improve feed efficiency, suppress estrus, and prevent and control coccidiosis due to Eimeria bovis and Eimeria zuernii. See NADA 124-309, 125-476, and 200-422.        c) With tylosin phosphate to increase the rate of weight gain, improve feed efficiency, suppress estrus, and reduce incidence of liver abscesses. See NADA 138-995, 139-192, and 200-427.        d) With lasalocid to increase the rate of weight gain, improve feed efficiency, and suppress estrus. See NADA 139-876, 140-288, and 200-451.        e) With monensin sodium and tylosin phosphate to increase the rate of weight gain, improve feed efficiency, suppress estrus, prevent and control coccidiosis due to Eimeria bovis and Eimeria zuernii, and reduce incidence of liver abscesses caused by Fusobacterium necrophorum and Actinomyces (Corynebacterium) pyogenes. See NADA 138-792, 138-870, and 200-375.        f) With tylosin phosphate and lasalocid to increase the rate of weight gain, improve feed efficiency, suppress estrus, and reduce incidence of liver abscesses. See NADA 138-904, 138-992, and 200-430.        g) With monensin sodium and ractopamine hydrochloride to increase the rate of weight gain, improve feed efficiency, suppress estrus, increase carcass leanness, and prevent and control coccidiosis due to Eimeria bovis and Eimeria zuernii. See NADA 141-234 and 200-448.        h) With monensin sodium, tylosin phosphate, and ractopamine hydrochloride to increase the rate of weight gain, improve feed efficiency, suppress estrus, increase carcass leanness, prevent and control coccidiosis due to Eimeria bovis and Eimeria zuernii, and reduce liver abscesses caused by Fusobacterium necrophorum and Actinomyces (Corynebacterium) pyogenes. See NADA 141-233 and 200-424.U.S. Pat. No. 3,417,182 discusses using melengestrol acetate to control estrual periods and stimulate growth of domestic birds and other animals.        
There still exists a need for alternative methods and compositions for increasing the rate of weight gain and improving feed efficiency in animals, particularly animals raised for food, such as livestock, poultry, and/or fish. The following disclosure describes such methods and compositions.